Australian Infectious Diseases Research Centre, School of Chemistry & Molecular Biosciences, The University of Queensland, Brisbane, QLD, 4072, Australia.
Immunol Cell Biol. 2020 Nov;98(10):819-831. doi: 10.1111/imcb.12389. Epub 2020 Sep 16.
Purines play an integral role in cellular processes such as energy metabolism, cell signaling and encoding the genetic makeup of all living organisms-ensuring that the purine metabolic pathway is maintained across all domains of life. To gain a deeper understanding of purine biosynthesis via the de novo biosynthetic pathway, the genes encoding purine metabolic enzymes from 35 archaean, 69 bacterial and 99 eukaryotic species were investigated. While the classic elements of the canonical purine metabolic pathway were utilized in all domains, a subset of familiar biochemical roles was found to be performed by unrelated proteins in some members of the Archaea and Bacteria. In the Bacteria, a major differentiating feature of de novo purine biosynthesis is the increasing prevalence of gene fusions, where two or more purine biosynthesis enzymes that perform consecutive biochemical functions in the pathway are encoded by a single gene. All species in the Eukaryota exhibited the most common fusions seen in the Bacteria, in addition to new gene fusions to potentially increase metabolic flux. This complexity is taken further in humans, where a reversible biomolecular assembly of enzymes known as the purinosome has been identified, allowing short-term regulation in response to metabolic cues while expanding on the benefits that can come from gene fusion. By surveying purine metabolism across all domains of life, we have identified important features of the purine biosynthetic pathway that can potentially be exploited as prospective drug targets.
嘌呤在细胞过程中发挥着重要作用，如能量代谢、细胞信号传递和编码所有生物体的遗传构成——确保嘌呤代谢途径在所有生命领域得以维持。为了更深入地了解从头生物合成途径中的嘌呤生物合成，研究了来自 35 种古菌、69 种细菌和 99 种真核生物的嘌呤代谢酶编码基因。虽然经典的嘌呤代谢途径的经典元素在所有领域都得到了利用，但在一些古菌和细菌中，发现一些熟悉的生化作用是由相关蛋白质来完成的。在细菌中，从头嘌呤生物合成的一个主要区别特征是基因融合的日益流行，其中两个或更多在途径中执行连续生化功能的嘌呤生物合成酶由单个基因编码。真核生物的所有物种都表现出与细菌中最常见的融合，此外还有新的基因融合，以潜在增加代谢通量。这种复杂性在人类中进一步发展，其中已经鉴定出一种称为嘌呤体的酶的可逆生物分子组装，允许根据代谢线索进行短期调节，同时扩大基因融合带来的益处。通过对所有生命领域的嘌呤代谢进行调查，我们确定了嘌呤生物合成途径的重要特征，这些特征可能被用作有前途的药物靶点。
